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ABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Placental Handling of Fatty Acid Ethyl Esters: Perfusion and Subcellular Studies

Division of Clinical Pharmacology and Toxicology, The Hospital for Sick Children, Toronto, Ontario (D.C., B.K., R.B., G.K.); and Department of Pharmacology, University of Toronto, Toronto, Ontario, Canada (D.C., G.K.)

The measurement of fatty acid ethyl esters (FAEE) in neonatal meconium is a novel test to confirm prenatal ethanol exposure. The origin of FAEE in the maternal-placental-fetal unit is not known. The objectives of this study were to investigate whether FAEE are transferred and metabolized by the human placenta. Isolated placental cotyledons were perfused with a mixture of four FAEE (palmitic, stearic, oleic, and linoleic acid ethyl esters) commonly detected in the meconium of neonates exposed to ethanol in utero, and the transfer of FAEE to the fetal unit was investigated in the absence and presence of albumin. The metabolic degradation of FAEE by human placental microsomes was subsequently determined. FAEE disappeared from the maternal circulation but remained undetectable in the fetal unit following perfusions. The addition of albumin had no effect on FAEE transfer. The unrecoverable fraction of individual FAEE in the perfusion system accounted for >50% of the initial amount used, suggesting significant metabolic degradation. Subcellular studies documented the enzymatic degradation of FAEE by placental microsomes (mean K_m, 35–95 µM; V, _max 0.6–1.8 nmol/min/mg for individual FAEE). FAEE at levels found in alcoholics that are originated from the mother are not transferred to the fetus because they are taken up and degraded extensively by the human placenta. Hence, FAEE detected in neonatal matrices are likely produced by the fetus from ethanol that has been transferred to and metabolized by the fetus, rendering FAEE a powerful direct biomarker reflective of true fetal exposure to ethanol in utero.

Address correspondence to: Dr. Gideon Koren, Division of Clinical Pharmacology and Toxicology, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, Canada M5G 1X8. E-mail: gkoren{at}sickkids.ca